Inhibitors in Hemophilia B

Abstract

Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.

Hemofilia B o enfermedad de Christmas

“…Los inhibidores son anticuerpos policlonales (principalmente de tipo IgG) de alta afinidad que inhiben la función de los factores de coagulación [60], y pueden surgir como aloanticuerpos en pacientes que han recibido transfusiones de factor IX exógeno [61], los cuales tienen especificidad contra los dominios Gla y serina proteasa del factor IX [62]. La prevalencia del desarrollo de inhibidores en pacientes con hemofilia B es menor que en pacientes con hemofilia A; en hemofilia B seve-ra es de aproximadamente 1,5% a 3% [60], y en hemofilia B moderada y leve es extremadamente raro el desarrollo de inhibidores [62]. Existen varios factores predisponentes para el desarrollo de inhibidores, como son el tipo de mutación genética involucrada [60,63], la edad del paciente y el número de infusiones de factores (en las primeras 50 infusiones existe mayor riesgo) [40].…”

“…La prevalencia del desarrollo de inhibidores en pacientes con hemofilia B es menor que en pacientes con hemofilia A; en hemofilia B seve-ra es de aproximadamente 1,5% a 3% [60], y en hemofilia B moderada y leve es extremadamente raro el desarrollo de inhibidores [62]. Existen varios factores predisponentes para el desarrollo de inhibidores, como son el tipo de mutación genética involucrada [60,63], la edad del paciente y el número de infusiones de factores (en las primeras 50 infusiones existe mayor riesgo) [40]. Debe sospecharse un inhibidor si un paciente tiene mal control del sangrado con el uso de factores o si tiene niveles de factores significativamente más bajos de lo previsto, posteriores a la infusión.…”

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia

“…Antibody formation directed at the newly-introduced proteins represents a serious complication in protein replacement therapy for the X-linked bleeding disorder hemophilia (1)(2)(3)(4)(5). One partial remedy is ITI ("immune tolerance induction, " consisting of daily high-dose intravenous infusion of FVIII), which however may take months to years and can cost >$1M (1).…”

“…Incidence of inhibitor formation against FIX is lower in treatment of hemophilia B (estimated ∼5% of patients). However, up to 50% of patients with FIX inhibitors experience anaphylactic reactions and/or nephrotic syndrome upon further exposure to FIX (4).…”

Syndromic cases of hemophilia B and morbid obesity due to contiguous gene deletions on Xq26.3-q27.2: unsuspected phenotype-genotype associations by bioinformatics and extensive clinical data mining

“…Nevertheless, all cases with entire F9 deletions showed FIX:C<1%. Development of inhibitory antibodies against exogenous FIX (inhibitors) is an important complication for patient's treatment and while HB cases show inhibitor frequencies ranging 1.4-11.7%, patients with complete F9 deletions may show >20% (Radic et al 2013;Santoro et al 2018;Thorland et al 1999). But in F9 , as in most human genes, both partial and complete gene deletions are uncommon (Ketterling et al 1994).…”